Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring

Valentina Pucino, Michelangelo Certo, Vinay Bulusu, Danilo Cucchi, Katriona Goldmann, Elena Pontarini, Robert Haas, Joanne Smith, Sarah E Headland, Kevin Blighe, Massimiliano Ruscica, Frances Humby, Myles J Lewis, Jurre J Kamphorst, Michele Bombardieri, Costantino Pitzalis, Claudio Mauro

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)
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Abstract

Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.

Original languageEnglish
Pages (from-to)1055-1074.e8
JournalCell Metabolism
Volume30
Issue number6
Early online date7 Nov 2019
DOIs
Publication statusPublished - 3 Dec 2019

Keywords

  • lactate
  • lactate transporter
  • signaling
  • inflammation
  • immunometabolism
  • T cell
  • translational research
  • cytokines
  • metabolic crosstalk

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